US7229636B1 - Cyanocobalamin low viscosity aqueous formulations for intranasal delivery - Google Patents
Cyanocobalamin low viscosity aqueous formulations for intranasal delivery Download PDFInfo
- Publication number
- US7229636B1 US7229636B1 US10/787,385 US78738504A US7229636B1 US 7229636 B1 US7229636 B1 US 7229636B1 US 78738504 A US78738504 A US 78738504A US 7229636 B1 US7229636 B1 US 7229636B1
- Authority
- US
- United States
- Prior art keywords
- cyanocobalamin
- solution
- concentration
- aqueous solution
- vitamin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime, expires
Links
- RMRCNWBMXRMIRW-BYFNXCQMSA-M cyanocobalamin Chemical compound N#C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O RMRCNWBMXRMIRW-BYFNXCQMSA-M 0.000 title claims abstract description 298
- 235000000639 cyanocobalamin Nutrition 0.000 title claims abstract description 149
- 239000011666 cyanocobalamin Substances 0.000 title claims abstract description 149
- 229960002104 cyanocobalamin Drugs 0.000 title claims abstract description 149
- 239000013011 aqueous formulation Substances 0.000 title 1
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- 229930003779 Vitamin B12 Natural products 0.000 claims abstract description 39
- 235000019163 vitamin B12 Nutrition 0.000 claims abstract description 39
- 239000007864 aqueous solution Substances 0.000 claims abstract description 35
- 238000010255 intramuscular injection Methods 0.000 claims abstract description 29
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 24
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- FDJOLVPMNUYSCM-WZHZPDAFSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+3].N#[C-].N([C@@H]([C@]1(C)[N-]\C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C(\C)/C1=N/C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C\C1=N\C([C@H](C1(C)C)CCC(N)=O)=C/1C)[C@@H]2CC(N)=O)=C\1[C@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]1[C@@H](O)[C@@H](N2C3=CC(C)=C(C)C=C3N=C2)O[C@@H]1CO FDJOLVPMNUYSCM-WZHZPDAFSA-L 0.000 claims abstract description 5
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 53
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 42
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- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 23
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- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 18
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
Definitions
- Vitamin B12 is a dietary essential, a deficiency of which results in defective synthesis of DNA in any cell in which chromosomal replication and division are taking place. Since tissues with the greatest rate of cell turnover show the most dramatic changes, the hematopoietic system is especially sensitive to vitamin B12 deficiencies. An early sign of B12 deficiency is a megaloblastic anemia. Dietary B12, in the presence of gastric acid and pancreatic proteases, is released from food and salivary binding protein and bound to gastric intrinsic factor. When the vitamin B12-intrinsic factor complex reaches the ileum, it interacts with a receptor on the mucosal cell surface and is actively transported into circulation.
- Vitamin B12 deficiency in adults is rarely the result of a deficient diet; rather, it usually reflects a defect in one or another aspect of this complex sequence of absorption.
- Achlorhydria and decreased secretion of intrinsic factor by parietal cells secondary to gastric atrophy or gastric surgery is a common cause of vitamin B12 deficiency in adults.
- Antibodies to parietal cells or intrinsic factor complex also can play a prominent role in producing deficiency. A number of intestinal diseases can interfere with absorption.
- Vitamin B12 malabsorption is seen with pancreatic disorders (loss of pancreatic protease secretion), bacterial overgrowth, intestinal parasites, sprue, and localized damage to ileal mucosal cells by disease or as a result of surgery.
- the recommended daily intake of vitamin B12 in adults is 2.4 ⁇ g.
- vitamin B 12 There are four main forms of vitamin B 12 : cyanocobalamin: hydroxocobalamin, methylcobalamin and adenosylcobalamin. Methylcobalamin and adenosylcobalamin are unstable and damaged by light. They are therefore unsuitable for use in dietary supplements or pharmaceuticals and are not essential since they can be formed from cyanocobalamin or hydroxocobalamin within the body.
- the main form of vitamin B 12 found in food is hydroxocobalamin.
- the main form used therapeutically and in nutritional supplements is cyanocobalamin, chosen because it is the most stable form and therefore easiest to synthesize and formulate.
- vitamin B12 Because deficiencies of vitamin B12 are generally caused by the inability of the vitamin to be absorbed in the small intestine due to a breakdown in the vitamin B12-intrinsic factor complex transport mechanism, vitamin B12 must therefore be administered systemically.
- therapeutic amounts of cyanocobalamin are administered by intramuscular or deep subcutaneous injection of cyanocobalamin.
- patients must return to the physician's office periodically to receive additional injections to maintain their levels of vitamin B12.
- an intranasal gel cyanocobalamin preparation, NASCOBAL® is currently being marketed in which cyanocobalamin is administered intranasally as maintenance vitamin B12 therapy.
- NASCOBAL® is currently being marketed in which cyanocobalamin is administered intranasally as maintenance vitamin B12 therapy.
- many patients find the consistency of the intranasal gel unpleasant and would prefer to have administered intranasally a low viscosity spray containing cyanocobalamin.
- Merkus developed intranasal formulations of hydroxocobalamin having a concentration of hydroxocobalamin greater than 1%, however hydroxocobalamin is not very stable and thus has a short shelve-life. Merkus chose hydroxocobalamin because cyanocobalamin is not soluble in an aqueous solution at concentrations greater than 1%.
- U.S. Pat. No. 4,525,341, Deihl discloses a method of administering vitamins intranasally but do not enable a specific formulation containing only cyanocobalamin.
- International Patent Application No. PCT/US86/00665, publication no. WO 86/05987, and European Patent Application No. EP0218679B1 discloses nasal spray composition containing vitamin B 12 as cyanocobalamin.
- the specific spray formulations all contained a mercury compound as a preservative, however the disclosure did require the presence of mercury compounds.
- Other preservatives were also mentioned including benzalkonium chloride and chlorobutanol.
- an intranasal gel containing cyanocobalamin is currently being produced and marketed by Nastech Pharmaceutical Company Inc. of Bothell, Wash. It is very effective in maintaining levels of vitamin B12 for patients who have been deficient in the past but have recovered their levels of B12 through intramuscular injections. However, a number of patients find the consistency of the gel unpleasant in their nose, and would prefer an intranasal formulation that has a lower viscosity and is free of mercury compounds. Thus, there is a need to produce a pharmaceutically stable aqueous solution of cyanocobalamin that has a low viscosity, is free of mercury compounds and has sufficient bioavailability to be used as a maintenance therapy for vitamin B12.
- the present invention fills this need by providing for a stable pharmaceutical solution of cyanocobalamin suitable for intranasal administration, having a viscosity less than about 1000 cPs, wherein said intranasal solution of cyanocobalamin has a bioavailability of at least 7% of the bioavailability of an intramuscular injection of cyanocobalamin and is free of mercury compounds.
- a preferred formulation is comprised of cyanocobalamin, citric acid, sodium citrate, and water wherein the viscosity is less than 1000 cPs, and wherein the solution of cyanocobalamin has a bioavailability of at least 8%, more preferably at least about 9, 10, 11, or 12% of the bioavailability of an intramuscular injection of cyanocobalamin.
- compositions within the scope of this invention will contain a humectant to inhibit drying of the mucous membranes and to prevent irritation.
- a humectant to inhibit drying of the mucous membranes and to prevent irritation.
- Any of a variety of humectants can be used including but not limited to sorbitol, propylene glycol or glycerol.
- a preferred humectant is glycerin.
- a preservative is generally employed to increase the shelf life of the compositions.
- preservative include but are not limited to benzyl alcohol, chlorobutanol and benzalkonium chloride.
- a preferred preservative is benzalkonium chloride.
- a suitable concentration of the preservative will be from 0.002% to 2.0% based upon the total weight, although there may be appreciable variation depending upon the agent selected.
- a most preferred formulation has the concentration of cyanocobalamin at 0.5% (percent of total weight), citric acid 0.12%, sodium citrate 0.32%, glycerin 2.23%, benzalkonium chloride 0.02% and 96.79% water.
- Another embodiment of the present invention is a method for administering cyanocobalamin comprised of infusing the nose with an aqueous solution of cyanocobalamin, wherein the solution of cyanocobalamin has a viscosity of less than 1000 cPs, and wherein said solution of cyanocobalamin has a bioavailability of at least about 7% relative to an intramuscular injection of cyanocobalamin.
- the bioavailability is at least 8%, 9%, 11% or 12%.
- the present invention is further directed towards a method for elevating the vitamin B12 levels in the cerebral spinal fluid (CSF) comprising intranasally administering a solution of cyanocobalamin so as to increase the average ratio of vitamin B12 in the CSF to that in the blood serum (B12 CSF/B12 Serum ⁇ 100) to at least about 1.1, wherein said solution of cyanocobalamin has a bioavailability of at least 7% relative to an intramuscular injection of cyanocobalamin.
- the B12 CSF levels are increased so that the ratio of B12 in the CSF to the levels in the blood serum is at least 1.9.
- “About” is taken to be a relative term denoting an approximation of plus or minus 20% of the nominal value it refers to. For the field of pharmacology and clinical medicine and analogous arts that are the subject of this disclosure, this level of approximation is appropriate unless the value is specifically stated to be critical or to require a tighter range.
- “Aqueous” refers to a solution formed in water, but may contain lesser amounts of other co-solvents.
- Bioavailability is defined as the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action, [21 CFR ⁇ 320.1(a)]. “Bioavailability of the intranasal spray relative to an intramuscular injection of cyanocobalamin” means the percent amount a dose of the intranasal taken up by the systemic vascular system in comparison to the same amount of cyanocobalamin injected.
- cyanocobalamin containing 100 ⁇ g of cyanocobalamin would have a 100% bioavailability
- an intranasal dose of cyanocobalamin contains 100 ⁇ g and has at least 7% bioavailability relative to an injection of cyanocobalamin
- at least 7 ⁇ g of cyanocobalamin would be taken up into the blood vasculature.
- the intranasal dose of cyanocobalamin contained 500 ⁇ g
- at least 35 ⁇ g of cyanocobalamin would be taken up into the blood vasculature, if the intranasal formulation had a bioavailability of at least 7%.
- “Stability” during storage, any compositional change measured in a parameter, examples of which include but are not limited to concentration, degradation, viscosity, pH, or particle size, that is considered to significantly affect the quality attributes of the product over time, denotes instability. In a similar vein, changes that are not considered to significantly affect the quality attributes of the product connote stability. The time period over which stability is measured is relative depending on the intended utility of the composition. Accelerated stability at higher temperature is sometimes taken as a more speedy way of extrapolating stability over longer periods of time than are actually measured. “Pharmaceutically acceptable”: refers to a composition which when administered to a human or a mammal by the indicated route of administration, provokes no adverse reaction which is disproportionate to the benefit gained by administration of said compound.
- “Mammal” shall include any of a class of warm-blooded higher vertebrates that nourish their young with milk secreted by mammary glands and have skin usually more or less covered with hair, and non-exclusively includes humans and non-human primates, their children, including neonates and adolescents, both male and female, livestock species, such as horses, cattle, sheep, and goats, and research and domestic species, including dogs, cats, mice, rats, guinea pigs, and rabbits. “Patient” or “subject” is used herein interchangeably with “mammal.” “Intranasal delivery” shall mean delivery of a drug primarily via the mucosa of the nasal cavity. This includes the superior, middle and inferior nasal turbinates and the nasal pharynx.
- “Substantially free” refers to the level of a particular active ingredient in the compositions of the invention, wherein the particular active ingredient constitutes less than 20%, preferably less than 10%, more preferably less than 5%, and most preferably less than 1%, by weight based on the total weight of active ingredients in the composition.
- Delivery vehicles herein found useful include actuator dispensers commonly used for nasal solutions and gels. Embodiments of this technology include multiple, single-dose, metered dose, child resistant, and disposable dispensers, and their kits.
- peak concentration (C max ) of cyanocobalamin in a blood plasma “area under concentration vs. time curve (AUC) of cyanocobalamin in a blood plasma”, “time to maximal plasma concentration (t max ) of vitamin in a blood plasma” are pharmacokinetic parameters known to one skilled in the art. [Laursen et al., Eur. J. Endocrinology, 135: 309-315, (1996)].
- the “concentration vs. time curve” measures the concentration of cyanocobalamin in a blood serum of a subject vs. time after administration of a dosage of cyanocobalamin to the subject either by intranasal, subcutaneous, or other parenteral route of administration.
- C max is the maximum concentration of cyanocobalamin in the blood serum of a subject following a single dosage of cyanocobalamin to the subject.
- t max is the time to reach maximum concentration of cyanocobalamin in a blood serum of a subject following administration of a single dosage of cyanocobalamin to the subject.
- AUC area under concentration vs. time curve
- the present invention provides improved methods and compositions for intranasal delivery cyanocobalamin to mammalian subjects for treatment or prevention of a variety of diseases, disorders and conditions.
- appropriate mammalian subjects for treatment and prophylaxis according to the methods of the invention include, but are not restricted to, humans and non-human primates, livestock species, such as horses, cattle, sheep, and goats, and research and domestic species, including dogs, cats, mice, rats, guinea pigs, and rabbits.
- the patient should receive daily intramuscular injections of 100 ⁇ g of cyanocobalamin for about 1 to 2 weeks, together with 1 to 5 mg of folic acid.
- Intramuscular injections of cyanocobalamin should not be greater than 100 ⁇ g as doses in excess of 100 ⁇ g are rapidly cleared from the plasma into the urine, and administration of larger amounts of vitamin B12 will not result in greater retention of larger amounts of the vitamin.
- the cyanocobalamin nasal spray of the present invention is directed towards the maintenance of the hematological status of patients who are in remission following intramuscular vitamin B12 therapy. So instead of a once a month injection of 100 ⁇ g of cyanocobalamin, using the cyanocobalamin spray, the patient self-administers a dose of the nasal spray of the present invention containing 500 ⁇ g of cyanocobalamin once or twice a week.
- the maintenance therapy of the intranasal cyanocobalamin is for any patient that had been diagnosed with a vitamin B12 deficiency, but especially for those treated for pernicious anemia and dietary deficiency of vitamin B12 occurring in strict vegetarians, the so-called vegans who eat no animal products.
- Maintenance cyanocobalamin therapy using the cyanocobalamin solution of the present invention is also indicated for those afflicted with malabsorption of vitamin B12 resulting from structural or functional damage to the stomach, where intrinsic factor is secreted or to the ileum, where intrinsic factor facilitates B12 absorption.
- These conditions include tropical sprue and nontropical sprue (Idiopathic steatorrhea, gluten-induced enteropathy).
- Maintenance cyanocobalamin therapy using the cyanocobalamin solution of the present invention is also indicated for those afflicted with malabsorption of vitamin B12 resulting from inadequate secretion of intrinsic factor, resulting from lesion that destroys the gastric mucosa (ingestion of corrosives, extensive neoplasia), and a number of conditions associated with a variable degree of gastric atrophy (such as multiple sclerosis, human immunodeficiency viral (HIV) infection certain endocrine disorders, iron deficiency, and subtotal gastrectomy).
- Structural lesions that lead to B12 deficiency include ileitis, ileal resections, Crohn's disease and malignancies.
- Vitamin B12 deficiencies may also be the result of competition by intestinal parasites, and inadequate utilization of vitamin B12 occurring if antimetabolites for the vitamin are employed in the treatment of neoplasia.
- the intranasal cyanocobalamin solution of the present invention can also be used for individual who require above normal levels of vitamin B12, due to for example pregnancy, thyrotoxicosis, hemolytic anemia, hemorrhage, malignancy, hepatic and renal disease.
- the present invention provides for a stable pharmaceutical solution of cyanocobalamin suitable for intranasal administration, having a viscosity less than about 1000 cPs, wherein said intranasal solution of cyanocobalamin has when administered intranasally a bioavailability of at least 7% of the bioavailability of an intramuscular injection of cyanocobalamin.
- the intranasal formulation will generally be comprised of in addition to water and cyanocobalamin, a buffering agent to maintain the pH between 4 and 6 preferably about 5, a humectanct to inhibit drying of the mucous membranes and a preservative.
- a preferred formulation is comprised of cyanocobalamin, citric acid, sodium citrate, and water wherein the viscosity is less than 1000 cPs, and wherein the solution of cyanocobalamin has a bioavailability of at least 7%, more preferably at least about 8, 9, 10, 11, 12% or more of the bioavailability of an intramuscular injection of cyanocobalamin.
- compositions within the scope of this invention will contain a humectant to inhibit drying of the mucous membranes and to prevent irritation.
- a humectant to inhibit drying of the mucous membranes and to prevent irritation.
- Any of a variety of humectants can be used including, for example sorbitol, propylene glycol or glycerol.
- a preferred humectant is glycerin.
- a preservative is generally employed to increase the shelf life of the compositions.
- preservative include benzyl alcohol, parabens thimerosal, chlorobutanol, benzethonium chloride and benzalkonium chloride.
- a preferred preservative is benzalkonium chloride.
- a suitable concentration of the preservative will be from 0.002% to 2% based upon the total weight, although there may be appreciable variation depending upon the agent selected.
- a most preferred formulation has the concentration of cyanocobalamin at 0.5% (percent of total weight), citric acid 0.12%, sodium citrate 0.32%, glycerin 2.23%, benzalkonium chloride solution 0.02% and 96.79% water.
- buffering agent combination include but are not limited to:
- Another embodiment of the present invention is a method for administering cyanocobalamin comprised of infusing the nose with an aqueous solution of cyanocobalamin, wherein the solution of cyanocobalamin has a viscosity of less than 1000 cPs, and wherein said solution of cyanocobalamin has a bioavailability of at least 7% relative to an intramuscular injection of cyanocobalamin.
- the bioavailability is at least about 8, 9, 10, 11, 12% or more of the bioavailability of an intramuscular injection of cyanocobalamin.
- the present invention is further directed towards a method for elevating the vitamin B12 levels in the cerebral spinal fluid (CSF) comprising intranasally administering a solution of cyanocobalamin so as to increase the average ratio of vitamin B12 in the CSF to that in the blood serum (B12 CSF/B12 Serum ⁇ 100) to at least about 1.1, wherein said solution of cyanocobalamin has a bioavailability of at least 7% relative to an intramuscular injection of a cyanocobalamin.
- the B12 CSF levels are increased so that the ratio of B12 in the CSF to the levels in the blood serum is at least 1.9.
- vitamin B12 deficiency can result in irreversible damage to the nervous system.
- Progressive swelling of myelinated neurons, demyelination, and neuronal cell death are seen in the spinal column and cerebral cortex.
- This causes a wide range of neurological signs and symptoms, including paresthesias of the hands and feet, diminution of vibration and position senses with resultant unsteadiness, decreased deep tendon reflexes, and, in the later stages, confusion, moodiness, loss of memory, and even a loss of central vision.
- the patient may exhibit delusions, hallucinations, or even an overt psychosis.
- vitamin B12 deficiency Since the neurological damage can be dissociated from the changes in the hematopoietic, vitamin B12 deficiency must be considered as a possibility in elderly patients with dementia and psychiatric disorders, even if they are not anemic. Thus, the embodiment of the present invention directed towards increasing the level of vitamin B12 in the CSF can have tremendous benefit for neurological patients. Thus, intranasal administration of vitamin B12 can be used to treat such diseases as Alzheimer's disease, dementia, and multiple sclerosis.
- Citric Acid-Phosphate buffer Citric Acid anhydrous, USP 0.240 Dibasic Sodium Phosphate anhydrous 0.357 2) Acetate buffer Sodium Acetate anhydrous, USP 0.220 Acetic Acid, glacial, USP 0.064 3) Phosphate buffer Monobasic Potassium Phosphate anhydrous, 0.483 NF Dibasic Sodium Phosphate anhydrous 0.004
- the intranasal formulations of the present invention can be administered using any spray bottle or syringe.
- a preferred nasal spray bottle is the, “Nasal Spray Pump w/Safety Clip, Pfeiffer SAP #60548, which delivers a dose of 0.1 mL per squirt and has a diptube length of 36.05 mm. It can be purchased from Pfeiffer of America of Princeton, N.J.
- Nascobal® (Cyanocobalamin, USP) is a synthetic form of vitamin B 12 with equivalent vitamin B 12 activity.
- the chemical name is 5,6-dimethyl-benzimidazolyl cyanocobamide.
- Nascobal® (Cyanocobalamin, USP) is marketed as a self-administered nasal gel.
- the recommended dose of Nascobal® (Cyanocobalamin, USP) in subjects with vitamin B 12 malabsorption who are in remission following inject able vitamin B 12 therapy is 500- ⁇ g administered intranasally once weekly.
- Vitamin B 12 deficiency has a number of causes, including malabsorption of vitamin B 12 resulting from structural or functional damage to the gastrointestinal system and dietary deficiency of vitamin B 12 .
- the purposes of this study are to compare the bioequivalence of vitamin B12 nasal gel versus the nasal spray, and to evaluate the relative bioavailability of three preparations of vitamin B12 in a fasted state in normal healthy male and female subjects.
- Intranasal cyanocobalamin gel is approved for a dose of 500 ⁇ g.
- the current study also utilizes a cyanocobalamin nasal spray at the same 500 ⁇ g dose and an intramuscular dose of 100 ⁇ g.
- This study was a single-site, open-label, 3-way (3-treatment, 6-sequence) crossover, pharmacokinetic study of vitamin B 12 administered via intranasal (IN) spray (500- ⁇ g), IN gel (Nascobal®) (500- ⁇ g), and intramuscular (IM) injection (100- ⁇ g) in fasted normal healthy male and female subjects, as follows:
- Treatment A One IN spray administration of 500- ⁇ g vitamin B 12 .
- the intranasal formulation was comprised of a preferred embodiment of the present invention and contained cyanocobalamin at a concentration of 0.5% (percent of total weight), citric acid 0.12%, sodium citrate 0.32%, glycerin 2.23%, 50% benzalkonium chloride solution 0.04% and 96.79% water.
- Treatment B One IN gel administration of 500- ⁇ g vitamin B 12 (Nascobal®).
- Treatment C One IM administration of 100- ⁇ g vitamin B 12 .
- subjects assigned to Treatment A received a single IN spray administration of 500 ⁇ g of vitamin B 12 .
- Subjects assigned to Treatment B received a single IN gel administration of 500 ⁇ g of vitamin B 12 (Nascobal®).
- Subjects assigned to Treatment C received a single IM administration of 100 ⁇ g of vitamin B 12 . Doses were preceded by an overnight fast (i.e., at least 8 hours) from food (not including water) and were followed by a fast from food (not including water) for at least 4 hours post-dose.
- AUC is a measure of the extent of drug bioavailability and reflects the total amount of drug that reaches the systemic circulation.
- C max represents the maximum serum concentration obtained after drug administration and provides an indication that sufficient drug has reached the systemic circulation to provide a therapeutic response. In addition, C max provides warning of possible toxic drug levels.
- AUC 0-t Area under the concentration-time curve from time 0 to the time of last measurable concentration, calculated by the linear trapezoidal rule.
- Bioequivalence was evaluated for the test (Treatment A—Nasal Spray) versus the reference (Treatment B—Gel).
- An analysis of variance (ANOVA, Ref. 2) was performed and the 90% confidence intervals were generated for the ratio of test/reference.
- C max and AUC 0-t were natural log (log e ) transformed prior to analysis.
- the corresponding 90% confidence intervals for the geometric mean ratio were obtained by taking the antilog of the 90% confidence intervals for the difference between the means on the log scale.
- test (Treatment A) is non-inferior (with respect to the reference (Treatment B) if the lower bound of the 90% confidence intervals from log e -transformed C max , and AUC 0-t were greater than or equal to 80%. If the lower bound of the 90% confidence intervals from log e -transformed C max and AUC 0-t were less than 80%, it was assumed that non-inferiority could not be established.
- the relative bioavailability for the two IN formulations was 0.9715. Bioavailability when comparing Treatment A (spray) versus Treatment C (IM) was 0.6105, and 0.6284 when comparing Treatment B (gel) versus Treatment C (IM).
- the pharmacokinetic profiles of the spray formulation and the gel formulation were similar for C max (1480 pg/mL, 1670 pg/mL, respectively) and AUC 0-t (92000 pg*hr/mL, 97000 pg*hr/mL, respectively). Additionally, the median difference for T max between the spray and gel IN formulation was less than 15 minutes ( ⁇ 0.24). The C max value for the IM formulation was significantly higher than the C max values for the two IN formulations (p ⁇ 0.0001).
- Bioequivalence was established for the Vitamin B 12 IN spray with regard to the gel data based on C max and AUC 0-t .
- the 90% confidence intervals for the log e -transformed C max and AUC 0-t for the spray and gel formulations fell within the range of 80% to 125%. Additionally, non-inferiority can be assumed when comparing the two IN formulations because the lower bounds of the confidence intervals are greater than 80% for both AUC 0-t and C max .
- CSF cerebrospinal fluid
- each subject After each dosing, each subject underwent lumbar puncture only once, with the retrieval of a total 4.0 mL of CSF (4 tubes, 1.0 mL per tube).
- CSF 4 tubes, 1.0 mL per tube.
- One third of the subjects had a CSF sample collected at 60 minutes post dosing, one third of subjects had a CSF sample collected at 90 minutes post dosing, and one third of subjects had a CSF sample collected at 120 minutes post dosing
- the cerebrospinal fluid was evaluated for total Vitamin B12 content. It was the objective of the study described herein to measure the amount of Vitamin B 12 present in the blood and CSF following intramuscular (IM) and nasal administration.
- IM intramuscular
- Reference Product Cyanocobalamin 100 mcg intramuscular injection.
- Cyanocobalamin Injection USP is a sterile solution of cyanocobalamin (Vitamin B12) for intramuscular or subcutaneous injection. Each mL contains 1,000 mcg cyanocobalamin.
- the cyanocobalamin intranasal aqueous solution was a preferred formulation of the present invention and contained cyanocobalamin at a concentration of 0.5% (percent of total weight), citric acid 0.12%, sodium citrate 0.32%, glycerin 2.23%, 50% benzalkonium chloride solution 0.04% and 96.79% water.
- Vitamin B12 Nasal Spray is supplied as a 2.3 mL bottle to deliver one dose: 500 mcg/0.1 mL per dose.
- the subject was instructed to gently blow his/her nose.
- the subject remained in a seated position, and the primed IN applicator was inserted into the nostril by the subject, under the direction of the study staff.
- the contralateral nostril was closed with the forefinger.
- Subjects will also be instructed to tilt their heads slightly back for dosing and to return their heads to an upright position while sniffing in gently immediately following dosing.
- a 0.1 mL dose of vitamin B12 spray will be released into the nasal cavity. (A dose is a single application to one nostril.)
- Subjects must inform the staff if they sneeze or if the product drips out of their nose.
- Subjects will not be re-dosed if they sneeze or if the product drips out of their nose.
- Subjects will be instructed to refrain from blowing their nose for 1 hour following IN treatment.
- each subject After dosing, each subject underwent lumbar puncture, involving the retrieval of 4.0 mL of CSF (4 tubes, 1.0 mL per tube).
- CSF 4 tubes, 1.0 mL per tube.
- One third of subjects from each group will have a CSF sample collected at 60 minutes post dosing, one third of subjects will have a CSF sample collected at 90 minutes post dosing, and one third of subjects will have a CSF sample collected at 120 minutes post dosing.
- the Investigator positioned the patient appropriately in order to proceed with lumbar puncture.
- the lumbar area was prepared and draped in the usual aseptic fashion.
- Local anesthesia was utilized (1% xylocaine, 1-5 mL).
- a spinal needle (20 or 22G) was introduced into the spinal canal, at the level deemed appropriate by the Investigator.
- the CSF samples were collected 60, 90 or 120 minutes after administration.
- a total of 4.0 mL of CSF were collected from each patient, and distributed into 4 separate collection tubes. The tubes were appropriately labeled with a patient identifier and submitted for bioanalytical analysis.
- the spinal needle was removed.
- Vitamin B12 The levels of vitamin B12 were determined in both the CSF and blood serum using Vitamin B 12 concentrations in the CSF will be analyzed for Qualitative determination of Vitamin B 12 using a validated TOSOH Nex. 1A procedure.
- the average ratio (B12 CSF/B12 Serum ⁇ 100) ranged from 1.1 to 1.9 for those individuals receiving intranasal administration of vitamin B12 while those who received intramuscular injections of vitamin B12 had an average ratio ranging from 0.17 to 0.24. This is a surprising result in that intranasal administration only has about a 7-12% bioavailability in the blood serum relative to intramuscular injection of vitamin B12. This indicates that intranasal administration of vitamin B12 reaches the CSF much more effectively than by intramuscular injection.
- a 4000 g batch of a cyanocobalamin solution of the present invention which had a concentration of 500 mcg/0.1 g of solution.
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Abstract
Description
“Nasal mucosa”: the nasal mucosa is taken to be the lining of the vestibule of the nose, where vascularized, and extending interiorly to the boundaries of the oropharynx and sinuses.
“Aqueous”: refers to a solution formed in water, but may contain lesser amounts of other co-solvents.
“Bioavailability” is defined as the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action, [21 CFR §320.1(a)].
“Bioavailability of the intranasal spray relative to an intramuscular injection of cyanocobalamin” means the percent amount a dose of the intranasal taken up by the systemic vascular system in comparison to the same amount of cyanocobalamin injected. For example, assuming an intramuscular injection of a solution of cyanocobalamin containing 100 μg of cyanocobalamin would have a 100% bioavailability, if an intranasal dose of cyanocobalamin contains 100 μg and has at least 7% bioavailability relative to an injection of cyanocobalamin, at least 7 μg of cyanocobalamin would be taken up into the blood vasculature. Likewise, if the intranasal dose of cyanocobalamin contained 500 μg, at least 35 μg of cyanocobalamin would be taken up into the blood vasculature, if the intranasal formulation had a bioavailability of at least 7%.
“Stability”: during storage, any compositional change measured in a parameter, examples of which include but are not limited to concentration, degradation, viscosity, pH, or particle size, that is considered to significantly affect the quality attributes of the product over time, denotes instability. In a similar vein, changes that are not considered to significantly affect the quality attributes of the product connote stability. The time period over which stability is measured is relative depending on the intended utility of the composition. Accelerated stability at higher temperature is sometimes taken as a more speedy way of extrapolating stability over longer periods of time than are actually measured.
“Pharmaceutically acceptable”: refers to a composition which when administered to a human or a mammal by the indicated route of administration, provokes no adverse reaction which is disproportionate to the benefit gained by administration of said compound.
“Mammal” shall include any of a class of warm-blooded higher vertebrates that nourish their young with milk secreted by mammary glands and have skin usually more or less covered with hair, and non-exclusively includes humans and non-human primates, their children, including neonates and adolescents, both male and female, livestock species, such as horses, cattle, sheep, and goats, and research and domestic species, including dogs, cats, mice, rats, guinea pigs, and rabbits. “Patient” or “subject” is used herein interchangeably with “mammal.”
“Intranasal delivery” shall mean delivery of a drug primarily via the mucosa of the nasal cavity. This includes the superior, middle and inferior nasal turbinates and the nasal pharynx. Note that the olfactory region is concentrated in the superior (upper ⅓) of the nasal turbinates. Cilial action pushes material back toward the oropharynx, so material deposited in the nasal vestibule encounters the nasal mucosa before entering the throat.
“Substantially free” refers to the level of a particular active ingredient in the compositions of the invention, wherein the particular active ingredient constitutes less than 20%, preferably less than 10%, more preferably less than 5%, and most preferably less than 1%, by weight based on the total weight of active ingredients in the composition.
Delivery vehicles herein found useful include actuator dispensers commonly used for nasal solutions and gels. Embodiments of this technology include multiple, single-dose, metered dose, child resistant, and disposable dispensers, and their kits.
Current Nasal | |||
Solution | |||
Component | Quantity (% w/w) | ||
Cyanocobalamin, USP | 0.50 | ||
Citric acid anhydrous, USP | 0.12 | ||
Sodium citrate dihydrate, USP | 0.32 | ||
Glycerin, USP | 2.23 | ||
Benzalkonium chloride (50%), | 0.04 | ||
NF | |||
Purified water q.s. | 100.0 | ||
Alternative buffer systems and amounts that can be used for Cyanocobalamin Nasal Spray
Quantity (% w/w) | ||
1) Citric Acid-Phosphate buffer | |||
Citric Acid anhydrous, USP | 0.240 | ||
Dibasic Sodium Phosphate anhydrous | 0.357 | ||
2) Acetate buffer | |||
Sodium Acetate anhydrous, USP | 0.220 | ||
Acetic Acid, glacial, USP | 0.064 | ||
3) Phosphate buffer | |||
Monobasic Potassium Phosphate anhydrous, | 0.483 | ||
NF | |||
Dibasic Sodium Phosphate anhydrous | 0.004 | ||
The intranasal formulations of the present invention can be administered using any spray bottle or syringe. A preferred nasal spray bottle is the, “Nasal Spray Pump w/Safety Clip, Pfeiffer SAP #60548, which delivers a dose of 0.1 mL per squirt and has a diptube length of 36.05 mm. It can be purchased from Pfeiffer of America of Princeton, N.J.
Treatment B: One IN gel administration of 500-μg vitamin B12 (Nascobal®).
Treatment C: One IM administration of 100-μg vitamin B12.
-
- The relative bioavailability for the two IN formulations was 0.9715. Bioavailability for Treatment A (spray) versus Treatment C (IM) was 0.6105, and 0.6284 when comparing Treatment B (gel) versus Treatment C (IM).
- The pharmacokinetic profiles of the spray formulation and the gel formulation are similar for Cmax (1480 pg/mL, 1670 pg/mL, respectively) and AUC0-t (92000 pg*hr/mL, 97000 pg*hr/mL, respectively). Additionally, the median difference for Tmax between the spray and gel IN formulation was less than 15 minutes (−0.24). The Cmax value for the IM formulation was significantly higher than the Cmax values for the two IN formulations (p<0.0001).
- Bioequivalence between the Vitamin B12 spray formulation and the Vitamin B12 gel formulation was established using loge-transformed 90% confidence intervals for AUC0-t and Cmax. The 90% confidence intervals for the loge-transformed Cmax and AUC0-t for the spray and gel formulations fell within the range of 0.80 to 1.25. Noninferiority can be assumed for the two IN formulations (Treatment A versus Treatment B).
- All Vitamin B12 formulations were safe and well tolerated by healthy male and female volunteers.
Starting Materials |
I. Formula Record |
Ingredient Name | Theoretical Weight (Grams) |
Cyanocobalamin, USP | 20.0 |
Citric Acid, USP (Anhydrous) | 4.8 |
Sodium Citrate, USP (Dihydrate) | 12.8 |
Glycerin, USP | 89.2 |
Benzalkonium Chloride Solution, NF (50%) | 1.6 |
Purified Water, USP | 3871.6* |
The 3871.6 grams of water was placed in a stainless steel container, which had been placed on a hot plate. The water was heated to about 30° C. and stirred. Into the heated water was added 12.8 g of sodium citrate while the water was being stirred at 300 rpm for 5 minutes. The 4.8 g of citric acid was then added and stirred for 10 minutes. Into this mixture was added 20.0 g of cyanocobalamin and stirred for 30 minutes at 30° C. at 300 rpm. The hot plate was then turned off. The 89.2 g of glycerin was added and stirred for 5 minutes at 300 rpm. Into the cyanocobalamin solution was then added 1.6 g of an aqueous solution containing 50% by weight of Benzalkonium Chloride was added to the solution and stirred for 5 minutes at 300 rpm. The pH was then measured and adjusted if the pH was not with the 4.5-5.5 range. Additional water was added to bring the weight of the solution to 4000 g.
Claims (31)
Priority Applications (6)
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US10/787,385 US7229636B1 (en) | 2003-03-04 | 2004-02-26 | Cyanocobalamin low viscosity aqueous formulations for intranasal delivery |
US10/814,399 US7404489B1 (en) | 2003-03-04 | 2004-03-31 | Cyanocobalamin low viscosity aqueous formulations for intranasal delivery |
US12/079,875 US7879349B2 (en) | 2003-03-04 | 2008-03-27 | Cyanocobalamin low viscosity aqueous formulations for intranasal delivery |
US12/142,240 US8003353B2 (en) | 2003-03-04 | 2008-06-19 | Cyanocobalamin low viscosity aqueous formulations for intranasal delivery |
US13/189,061 US8940714B2 (en) | 2003-03-04 | 2011-07-22 | Cyanocobalamin low viscosity aqueous formulations for intranasal delivery |
US14/485,228 US9415007B2 (en) | 2003-03-04 | 2014-09-12 | Cyanocobalamin low viscosity aqueous formulations for intranasal delivery |
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US45189903P | 2003-03-04 | 2003-03-04 | |
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US47420403P | 2003-05-29 | 2003-05-29 | |
US10/787,385 US7229636B1 (en) | 2003-03-04 | 2004-02-26 | Cyanocobalamin low viscosity aqueous formulations for intranasal delivery |
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US10/814,399 Continuation US7404489B1 (en) | 2003-03-04 | 2004-03-31 | Cyanocobalamin low viscosity aqueous formulations for intranasal delivery |
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080182817A1 (en) * | 2003-03-04 | 2008-07-31 | Qol Medical Llc | Cyanocobalamin low viscosity aqueous formulations for intranasal delivery |
US20090012039A1 (en) * | 2007-03-16 | 2009-01-08 | Stan Kurtz | Use of methylcobalamin nasal spray to treat disorders |
WO2012056299A1 (en) | 2010-10-29 | 2012-05-03 | Troikaa Pharmaceuticals Limited | Nasal compositions of vitamin b12 |
GB202013645D0 (en) | 2020-08-31 | 2020-10-14 | Innotesto Bvba | Pharmacetical compositions for the nasal administration of a colbalamin compound |
US11331334B2 (en) | 2017-02-06 | 2022-05-17 | Torrent Pharmaceuticals Ltd. | Intranasal composition of methylcobalamin |
Citations (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2703303A (en) | 1950-02-25 | 1955-03-01 | Merck & Co Inc | Production of l. l. d-active substances by streptomyces |
US2703302A (en) | 1952-12-08 | 1955-03-01 | Merck & Co Inc | Vitamin b12-active composition and process of preparing same |
US2746796A (en) | 1953-08-05 | 1956-05-22 | Pharma Craft Corp | Metering valve aerosol bottle |
US2914222A (en) | 1957-05-20 | 1959-11-24 | Meshberg Philip | Aerosol package |
US2951017A (en) | 1957-06-27 | 1960-08-30 | Distillers Co Yeast Ltd | Cobalamin producing fermentation process |
US3000793A (en) | 1957-01-22 | 1961-09-19 | Merck & Co Inc | Production of cobalamins |
US3018225A (en) | 1959-03-09 | 1962-01-23 | Merck & Co Inc | Production of vitamin b12 |
US3057851A (en) | 1959-04-13 | 1962-10-09 | Armour Pharma | Process for preparing vitamin b12 |
US3120508A (en) | 1959-08-20 | 1964-02-04 | Hoechst Ag | Process for the manufacture of waterinsoluble azo-dyestuffs |
US3282781A (en) | 1960-11-25 | 1966-11-01 | Merck & Co Inc | Inhalant compositions |
US3548057A (en) | 1969-04-29 | 1970-12-15 | Merck & Co Inc | Topical administration of vitamin b12 |
US3577537A (en) | 1970-03-09 | 1971-05-04 | Merck & Co Inc | Topical administration of vitamin b-12 |
US3584115A (en) | 1968-05-31 | 1971-06-08 | Arthur Ira Gebhart | Method of applying visible aerosol compositions |
US3957968A (en) | 1973-08-20 | 1976-05-18 | Colgate-Palmolive Company | Dentifrices containing flat flakes of alpha-alumina |
US4174295A (en) | 1976-08-13 | 1979-11-13 | Montedison S.P.A. | Aerosol propellant compositions |
EP0130550A2 (en) | 1983-06-29 | 1985-01-09 | Intermedicat GmbH | Pharmaceutical compositions based on heparin and surfactants having an effect on the mucous membranes of the mouth, the nose and/or the throat |
EP0131315A2 (en) | 1983-05-13 | 1985-01-16 | ISTITUTO DE ANGELI S.p.A. | Nasal preparations comprising anticholinergic quaternary ammonium salts |
US4525341A (en) | 1984-04-09 | 1985-06-25 | Mayor Pharmaceutical Laboratories, Inc. | Method of administering vitamins |
WO1986005988A1 (en) | 1985-04-16 | 1986-10-23 | Nastech Pharmaceutical Company, Inc. | Nasal compositions containing vitamin b12 |
WO1986005987A1 (en) | 1985-04-16 | 1986-10-23 | Nastech Pharmaceutical Company, Inc. | Aerosol compositions for nasal delivery of vitamin b12 |
US4727231A (en) | 1985-10-01 | 1988-02-23 | Doryokuro Kakunenryo Kaihatsu Jigyodan | Method and apparatus for denitration of nitrate solution by microwave heating |
US5797390A (en) | 1996-03-06 | 1998-08-25 | Mcsoley; Thomas E. | Nasal inhaler having a directed spray pattern |
US5801161A (en) | 1993-12-20 | 1998-09-01 | Merkus; Franciscus W. H. M. | Pharmaceutical composition for the intranasal administration of hydroxocobalamin |
US5825625A (en) | 1996-05-20 | 1998-10-20 | Hewlett-Packard Company | Heat conductive substrate mounted in PC board for transferring heat from IC to heat sink |
US6685421B1 (en) | 2003-01-02 | 2004-02-03 | Charles N. Reeves | Hitch-mounted lift assembly |
-
2004
- 2004-02-26 US US10/787,385 patent/US7229636B1/en not_active Expired - Lifetime
Patent Citations (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2703303A (en) | 1950-02-25 | 1955-03-01 | Merck & Co Inc | Production of l. l. d-active substances by streptomyces |
US2703302A (en) | 1952-12-08 | 1955-03-01 | Merck & Co Inc | Vitamin b12-active composition and process of preparing same |
US2746796A (en) | 1953-08-05 | 1956-05-22 | Pharma Craft Corp | Metering valve aerosol bottle |
US3000793A (en) | 1957-01-22 | 1961-09-19 | Merck & Co Inc | Production of cobalamins |
US2914222A (en) | 1957-05-20 | 1959-11-24 | Meshberg Philip | Aerosol package |
US2951017A (en) | 1957-06-27 | 1960-08-30 | Distillers Co Yeast Ltd | Cobalamin producing fermentation process |
US3018225A (en) | 1959-03-09 | 1962-01-23 | Merck & Co Inc | Production of vitamin b12 |
US3057851A (en) | 1959-04-13 | 1962-10-09 | Armour Pharma | Process for preparing vitamin b12 |
US3120508A (en) | 1959-08-20 | 1964-02-04 | Hoechst Ag | Process for the manufacture of waterinsoluble azo-dyestuffs |
US3282781A (en) | 1960-11-25 | 1966-11-01 | Merck & Co Inc | Inhalant compositions |
US3584115A (en) | 1968-05-31 | 1971-06-08 | Arthur Ira Gebhart | Method of applying visible aerosol compositions |
US3548057A (en) | 1969-04-29 | 1970-12-15 | Merck & Co Inc | Topical administration of vitamin b12 |
US3577537A (en) | 1970-03-09 | 1971-05-04 | Merck & Co Inc | Topical administration of vitamin b-12 |
US3957968A (en) | 1973-08-20 | 1976-05-18 | Colgate-Palmolive Company | Dentifrices containing flat flakes of alpha-alumina |
US4174295A (en) | 1976-08-13 | 1979-11-13 | Montedison S.P.A. | Aerosol propellant compositions |
EP0131315A2 (en) | 1983-05-13 | 1985-01-16 | ISTITUTO DE ANGELI S.p.A. | Nasal preparations comprising anticholinergic quaternary ammonium salts |
EP0130550A2 (en) | 1983-06-29 | 1985-01-09 | Intermedicat GmbH | Pharmaceutical compositions based on heparin and surfactants having an effect on the mucous membranes of the mouth, the nose and/or the throat |
US4525341A (en) | 1984-04-09 | 1985-06-25 | Mayor Pharmaceutical Laboratories, Inc. | Method of administering vitamins |
WO1986005987A1 (en) | 1985-04-16 | 1986-10-23 | Nastech Pharmaceutical Company, Inc. | Aerosol compositions for nasal delivery of vitamin b12 |
WO1986005988A1 (en) | 1985-04-16 | 1986-10-23 | Nastech Pharmaceutical Company, Inc. | Nasal compositions containing vitamin b12 |
US4724231A (en) * | 1985-04-16 | 1988-02-09 | Nastech Pharmaceutical, Inc. | Nasel compositions containing vitamin B12 |
CA1317881C (en) | 1985-04-16 | 1993-05-18 | Jeffrey Wenig | Aerosol compositions for nasal delivery of vitamin b__ |
US4727231A (en) | 1985-10-01 | 1988-02-23 | Doryokuro Kakunenryo Kaihatsu Jigyodan | Method and apparatus for denitration of nitrate solution by microwave heating |
US5801161A (en) | 1993-12-20 | 1998-09-01 | Merkus; Franciscus W. H. M. | Pharmaceutical composition for the intranasal administration of hydroxocobalamin |
US5797390A (en) | 1996-03-06 | 1998-08-25 | Mcsoley; Thomas E. | Nasal inhaler having a directed spray pattern |
US5825625A (en) | 1996-05-20 | 1998-10-20 | Hewlett-Packard Company | Heat conductive substrate mounted in PC board for transferring heat from IC to heat sink |
US6685421B1 (en) | 2003-01-02 | 2004-02-03 | Charles N. Reeves | Hitch-mounted lift assembly |
Non-Patent Citations (21)
Title |
---|
A. Killander and I. Werner, Studies on Maintenance Treatment of Penicious Anaemia, Vitamin B<SUP>12 </SUP>and Intrinsic Factor Europaisches Symposian Hamburg, 1961, pp. 663-667, Ed. H.c. Heinrich, Enke, Stuttgart, Department of Pediatris and Internal Medicine, Akademiska, Sjukhuset, Uppsala, Sweden. |
Anthony J. Cutie and John J. Sciarra, Intranasal Pharmaceutical Aerosols, Aerosal Age, The International authority in Spray Packaging, Aerosol Age Magazine, Oct. 1982, pp. 1-4. |
Anwar A. Hussain, Yukihiko Aramaki, Studies on the Intranasal Absorption of vitamin B<SUP>12 </SUP>in the Rat, Final Report, Dec. 1984, University of Kentucky, College of Pharmacy, Lexington, KY, US. |
Cheng Der Yu, Richard Jones, Jim Wright, and Maida Henesian, Characterization of dose delivery and spray pattern of a metered-dose flunisolide nasel spray, Drug development and Industrial Pharmacy, 1983, 9(3), pp. 473-483, Institute of Pharmaceutical Sciences, Syntex Research, Palo Alto, CA Marcel Dekker, Inc., US. |
Edited by James E.F. Reynolds, Cyanocobalamin, Martindale, The Extra Pharmacopoeia, 1982, Abstract 7853-d, and Page 1645, Cyanocobalamin Injection, 28<SUP>th </SUP>Edition, Published by direction of the Council of The Pharmaceutical Society of Great Britain and prepared in the Society's Department of Pharmaceutical Sciences, The Pharmaceutical Press, London, UK. |
Forest Laboratories, Inc., Long Acting oral carrier, Chemical Abstracts, vol. 77, Year 1972, p. 263, Abstract 105623(y). |
Garcia-Arieta et al. Spray-Dried Powders as Nasal Absorption Enhancers of Cyanocobalamin., Dec. 2001., Biol. Pharm. Bull. 24(12) pp. 1411-1416. * |
Garcia-Arieta, A.; Torrado-Santiago, S.; Goya, L.; Torrado, J. J, . Spray-dried powers as nasal absorption enhancers of cyanocobalamin, Biol.Pharm.Bull, date- 2001, vol. 24, issue- 12, pp. 1411-1416, Pharmaceutical Society of Japan. |
John J. Siarra, Aerosols, Chapter 92, Year Unknown, pp. 1614-1621, Arnold & Marie Schwartz Collet of Pharmacy and Health Science, Long Island Univeristy, Brooklyn, NY, US. |
N.K. Shinton and A.K. Singh, Vitamin B<SUP>12 </SUP>absorption by inhalation, Brit. J. Haemat, 1967, 13. pp. 75-79, Department of Haematology, Coventry and Warwickshire Hospital, Coventry. |
N.K. Shinton and A.K. Singh, Vitamin B<SUP>12 </SUP>Absorption by Inhalation, Chemical Abstracts, vol. 66, No. 15, Coden: Chaba8, The American Chemical Society, Apr. 10, 1967, p. 6024, Abstract 64246(e) Northampton Sts, Easton, PA, US. |
R.K. Chandra, Gloria Heresi, and G. Woodford, Double-blind controlled crossover trial of 4% intranasal sodium cromoglycate solution in patients with seasonal allergic rhinitis, Annals of Allergy, Sep. 1982, vol. 49, From the Department of Pediatrics, Memorial University of Newfoundland, Janeway Child Health Ceneter and Health Sciences Center, St. John's , Newfoundland, Canada. |
Raymond W. Monto, John W. Rebuck, Michael Brennan, Crystalline B<SUP>12 </SUP>Inhallation Theraphy in Perniciouos Anemia, The American Journal of the Medical Sciences, Feb. 1953, pp. 113-119, Publisher: Division of Hematology and the Department of Laboratories, The Henry Ford Hospital, Detroit, Michicagn Published in: Detroit, MI, US. |
Raymond W. Monto, John W. Rebuck, Nasal Instiliation and Inhalation of Crystalline Vitimin B<SUP>12 </SUP>in Pernicious Anemia, A.M.A. Archives 6 Internal Medicine, vol. 93, 1954, From the Division of Hematology (Dr. Monto) and the Department of Laboratories (Dr. Rebuck), The Henry Ford Hospital. Pages 219-230. Detroit, MI, US. |
Raymond W. Monto, John W. Rebuck, Observations on the Mechanism of Intranasal Absorption of Vitamin B<SUP>12 </SUP>in Pernicious Anemia. Blood, vol. 10, 1955, pp. 1151-1155, From the Division of Hematology (Dr. Monto) and the Department of Laboratories (Dr. Rebuck), The Henry Ford Hosptial. Detroit, MI, US. |
Sally Mathison, Rakesh Nagilla, and Uday B. Kompella, Nasel Route for Direct delivery of Solutes to the Central Nervous System: Fact or Fiction? Journal of Drug Targeting, 1998, vol. 5, No. 6, pp. 415-441 Departement of Pharmacal Sciense, Department of Chemistry, Auburn University, Auburn, AL US. |
Slot et al. Normalization of Plasma Vitamin B12 Concentration by Intranasal Hydroxocobalamin in Vitamin B12 -Deficient Patients., (1997)., Gastroenterology 1997(113) pp. 430-433. * |
T.Q.Nijst, R.A. Wevers, H.C. Schoonderwaldt, O.R. Hommes, A.F.J. De Haan, Vitamin B12 and folate concentrations in serum and cerebrospinal fluid of neurological patients with special reference to multiple sclerosis and dementia, Journal of Neurology, Neurosugery, and Psychiatry, Year 1990; 53, pp. 951-954. |
U.S Department of Health and Human Services, (Draft) Guidance for Industry, Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action, Apr. 2003, pp. 1-36+ attachments, U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Biopharmaceutics. |
U.S. Department of Health and Humans Services, Guidance for Industry, Nasal spary and inhalation solution, suspension, and spray drug products-chemistry, manufacturing, and controls documentation, Jul. 2002, pp. 1-44, Food and Drug Administration, Center for Drug Evaluation and Research, Rockville, MD, US. |
Valois, Pumps for Pharmacy, Year Unknown (product brochure). |
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GB202013645D0 (en) | 2020-08-31 | 2020-10-14 | Innotesto Bvba | Pharmacetical compositions for the nasal administration of a colbalamin compound |
WO2022043526A1 (en) | 2020-08-31 | 2022-03-03 | Innotesto Bv | Pharmaceutical compositions for the nasal administration of a cobalamin compound |
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